An Integrin/MFG-E8 shuttle loads HIV-1 viral like particles onto follicular dendritic cells. During human immunodeficiency virus-1 (HIV-1) infection lymphoid organ follicular dendritic cells (FDCs) serve as a reservoir for infectious virus and an obstacle to curative therapies. In this study we identified a subset of lymphoid organ sinus lining macrophage (SMs) that provide a cell-cell contact portal, and a shuttling system, which facilitates the uptake of HIV-1 viral like particles (VLPs) by FDCs and B cells. Central for portal function was the bridging glycoprotein MFG-E8. Using a phosphatidylserine (PS) binding domain and an RGD motif, MFG-E8 helped target HIV-1 VLPs to v integrin bearing SMs. Both FDCs and HIV-1 gp120 specific B cells collected HIV-1 VLPs from MFG-E8 rich sites on SMs. Lack of MFG-E8 or integrin blockade severely limited the spread of HIV-1 VLPs onto FDC networks. Our results identify a mechanism for HIV-1 uptake by SMs that facilitates the cell to cell spread of HIV-1 to FDCs and B cells. Defining a CD38-LRRK2-TFEB pathway in B cells and macrophages. CD38 is a cell surface receptor highly expressed in B cells and macrophages responsible for generating several different second messengers. Leucine rich repeat kinase 2 (LRRK2) is a large multiple function protein expressed in B cells and macrophages, but not previously connected to CD38. LRRK2 is of clinical interest because mutations in it are linked to Parkinsons disease. We have found that CD38 ligation caused a calcium dependent nuclear translocation of transcription factor EB (TFEB) in B cells and macrophages. CD38 engagement triggers a bi-phasic calcium signal that depended upon extracellular and lysosomal calcium. CD38 and LRRK2 co-localized at the plasma membrane, and the two proteins robustly interacted by co-immunoprecipitation. Cells from LRRK2 null mice showed decreased calcium responses after CD38 stimulation, while cells from kinase overactive LRRK2 knock-in (KI) mice had the opposite phenotype. Consistent with these findings, LRRK2 null cells showed defects in TFEB activation following CD38 ligation. TFEB activation is known to help mediate the switch from oxidative phosphorylation to glycolysis in macrophages. Accordingly, LRRK2 null macrophages had decreased glycolytic activity after LPS stimulation, while LRRK2 KI macrophages had increased activity. Interestingly we also found that CD38 stimulation limits macrophage inflammasome induced IL-1 release, and this inhibition depended upon the presence of LRRK2. In sum, we have identified a previously unknown CD38-LRRK2-TFEB signaling axis with functional implications for both B cells and macrophages. Galphai2 signaling regulates inflammasome activity and cytokine production by biasing macrophage phenotype determination. Macrophages exist as innate immune subsets that exhibit phenotypic heterogeneity and functional plasticity. Several Galphai coupled GPCRs have been implicated in driving macrophage polarization. We used genetically modified mice to investigate the role of Galphai2 in inflammasome activity and macrophage polarization. We have shown that Gi2 in murine bone marrow-derived macrophages (BMDMs) regulates IL-1 release after inflammasome activation, independent of inflammasome type. This regulation stemmed from the biased polarity of Gi2 deficient (Gnai2/) and RGS-insensitive Galphai2 (Gnai2G184S/G184S) BMDMs. We determined that while Gnai2G184S/G184S BMDMs (lack Gi2/RGS protein interactions) have a tendency towards pro-inflammatory (M1) phenotype, Gnai2/ BMDMs (Galphai2 deficient) are biased towards anti-inflammatory (M2) phenotype. Long-term, but not short-term inhibition of Galphai2 with pertussis toxin recapitulated the KO phenotype, suggesting that the inflammatory changes are built into the macrophage life history. In summary, our data indicates that excess Galphai2 signaling promotes an M1 macrophage phenotype, while Galphai2 signaling deficiency promotes an M2 phenotype. Understanding Galphai2-mediated effects on macrophage polarization may bring to light insights regarding disease pathogenesis and the reprogramming of macrophages for the development of novel therapeutics. Bcl-2 regulates pyroptosis and necroptosis by targeting BH-3 like domains in gasdermin D and MLKL. Apoptosis is a form of programmed cell death in multicellular organisms. Bcl-2 prevents apoptosis and promotes cellular survival by neutralizing BH3 domain containing proteins, which directly activate the pore-forming proteins BAX and BAK. However, Bcl-2 is not known to regulate other cell death effectors such as gasdermin D (GSDMD) or mixed lineage kinase domain-like (MLKL), whose activation causes pyroptosis and necroptosis, respectively. In this study, we identified a BH3-like domain in both GSDMD and MLKL that mediates an interaction with Bcl-2. The presence of Bcl-2 reduced GSDMD cleavage at D275 by caspase-1, 4 or 5, and enhanced the GSDMD cleavage at D87. The GSDMD D87 cleavage inactivates the pyroptotic execution program. The presence of Bcl-2 also limited RIP3 mediated phosphorylation of MLKL, which reduced MLKL oligomerization and tempered the induction of necroptosis. Our observations suggest that the presence of Bcl-2 limits the induction of three forms of cell death apoptosis, pyroptosis, and necroptosis. AKT phosphorylates Serine 5 in NLRP3 affecting its oligomerization status and stability. The phosphorylation status of S5 is known to affect the oligomerization of NLRP3. The dephosphorylation of S5 by Phosphatase 2A triggers NLRP3 oligomerization and ASC recruitment. However, the protein kinase that mediates the S5 phosphorylation is unknown. In this study we showed that AKT phosphorylate NLRP3 at S5, thereby reducing NLRP3 oligomerization. In addition, the S5 phosphorylation prevented NLRP3 from Trim31 ubiquitin E3 ligase induced proteasome degradation. We identified lysine 496 in NLRP3 as the Trim31 ligase target. The K496R NLRP3 mutation reduced TRIM31 mediated ubiquitin proteasome degradation stabilizing NLRP3. Consistent with these studies treating mice with an AKT inhibitor enhanced NLRP3 inflammasome activity. We propose that AKT together with Phosphatase 2A to control the stability of NLRP3 and its activation threshold. SARS-CoV ORF8b triggers intracellular stress pathways and activates NLRP3 inflammasomes. SARS pathology is propagated both by direct cytotoxic effects of the virus and aberrant activation of the innate immune response. In this study we identified several mechanisms by which a SARS-CoV open reading frame (ORF) activates intracellular stress pathways and targets the innate immune response. We show that ORF8b forms insoluble intracellular aggregates, which depends on a valine at residue 77. Aggregated ORF8b induces endoplasmic reticulum (ER) stress, lysosomal damage, and subsequent activation of the master regulator of the autophagy and lysosome machinery, Transcription factor EB (TFEB). ORF8b causes cell death in epithelial cells, which is partially rescued by reducing its ability to aggregate. In macrophages, ORF8b robustly activates the NLRP3 inflammasome by providing both a weak signal 1 and potent signal 2 required for activation. Mechanistically, ORF8b interacts directly with the Leucine Rich Repeat domain of NLRP3 and localizes with NLRP3 and ASC in cytosolic dot-like structures. ORF8b triggers cell death consistent with pyroptotic cell death in macrophages. In contrast, in those cells that lack NLRP3, ORF8b accumulates as cytosolic aggregates cause ER stress, mitochondrial dysfunction, and caspase-independent cell death.